Natriuretic responses to water immersion or acute volume expansion with isotonic saline are diminished in diabetic patients indicating a defect in renal function and volume regulation in these individuals. However, specific intrarenal mechanisms involved in the altered renal excretory response to volume expansion in diabetes remain unidentified. Recently, the P.I. has confirmed that diabetic rats demonstrate a blunted natriuresis and diuresis in response to acute volume expansion (VE). Furthermore, renal denervation only partially improves the renal excretory response in diabetic rats. These results suggest that part of the blunted natriuretic response to VE in diabetic rats is mediated by non-neural mechanisms, a major component of which is likely intrarenal origin. Thus, their overall hypothesis is the intrarenal factors which drive the excretory response to acute volume expansion and altered in diabetic rats. Two key intrarenal factors that dictate sodium excretion during acute VE are renal medullary blood flow (MBF) and renal interstitial hydrostatic pressure (RIHP). Furthermore, preliminary data suggest that influence of nitric oxide (NO), atrial natriuretic factor (ANF) and renal nerves on renal excretory function are altered in diabetic rats. Hence, the present proposal is designed to determine; first if MBF and RIHP responses to VE are altered in diabetic rats, second if a defective renal nitric oxide (NO) system contributes to the altered are altered in diabetic rats, second if a defective renal nitric oxide (NO) system contributes to the altered MBF and RIHP responses to acute VE in diabetic rats, third if intrarenal mechanisms (MBF and RIHP) involved in the excretory response to ANF are altered in diabetic rats, fourth if intrarenal mechanisms (MBF and RIHP) are involved in the altered neural component of the excretory response to VE in diabetic rats. Successful completion of the proposed studies will provide added insight into the intrarenal mechanisms that disrupt fluid and electrolyte balance during the early stage of diabetes. Once they understand and identify the basic intrarenal mechanisms that are involved in this phenomenon during the early phase of diabetes, the long term goal would be to develop better strategies to treat and manage these abnormalities which would alleviate subsequent renal damage and cardiovascular complications commonly observed in the diabetic state.